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Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation
Brain & Development xxx (2017) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation Kotoha Harada a,⇑, Mayumi Yamamoto a, Yukihiko Konishi b, Kaori Koyano b, Satoru Takahashi c, Masanori Namba d, Takashi Kusaka b b
a Department of Pediatrics, Shodoshima Central Hospital, Japan Department of Pediatrics, Faculty of Medicine, Kagawa University, Japan c Department of Pediatrics, Asahikawa Medical University, Japan d Department of Pediatrics, Kagawa Rehabilitation Center, Japan
Received 12 January 2017; received in revised form 24 June 2017; accepted 17 July 2017
Abstract The forkhead box G1 (FOXG1) gene encodes a brain-specific transcription factor and is associated with a congenital variant of atypical Rett syndrome (RTT); several FOXG1 mutations have been identified. The congenital variant of RTT shows a hypoplastic corpus callosum, delayed myelination, and frontal and temporal atrophy. Although no report has described a hippocampal abnormality in humans, the current study suggests that FOXG1 also regulates neurogenesis in the postnatal hippocampus. In the present case, severe developmental delay was observed in a patient with a congenital variant of RTT from about 4 months, in conjunction with acquired microcephaly, hypotonia, limited motor function, absent purposeful hand use, and repetitive jerky movements of the upper limbs. A novel missense mutation was identified in FOXG1 on gene analysis (c. 569T>A, p. Ile190Asn). The patient showed not only the typical cerebral abnormalities of a congenital variant of RTT, but also a hypoplastic hippocampus. This novel mutation and cerebral findings may provide new insights into the pathophysiology of the congenital variant of RTT. Ó 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Rett syndrome; Congenital variant; Hypoplastic hippocampus; FOXG1; Novel missense mutation
1. Introduction Rett syndrome (RTT) is a neurodevelopmental disorder associated with diverse neurologic manifestations in an age-dependent manner. It is diagnosed based on clinical symptoms, and regression of purposeful hand use and language function, abnormal gait, and stereotypical movement of the hands are essential features. Patients
⇑ Corresponding author at: Department of Pediatrics, Shodoshima Central Hospital, 2060-1 Ikeda, Shodoshima-cho, Shozu-gun, Kagawa 761-4301, Japan. E-mail address: [email protected] (K. Harada).
whose clinical course shows similar but also different features are reported to have atypical RTT. In a type of atypical RTT, the congenital variant—caused by an aberrant forkhead box G1 (FOXG1) gene and now be considered as Rett-related disorders [1]—is present and developmental delay is observed soon after birth. In addition, acquired microcephaly, repetitive thrusting of the tongue, and stereotypical movements accompanied by jerky movements of the upper limbs are the main characteristics. A hypoplastic corpus callosum, delayed myelination, and frontal and temporal atrophy are the salient brain MRI features. No report has described a hippocampal abnormality. We identified a novel
http://dx.doi.org/10.1016/j.braindev.2017.07.007 0387-7604/Ó 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Harada K et al. Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.07.007
2
K. Harada et al. / Brain & Development xxx (2017) xxx–xxx
A
B
D
C
E
F
Fig. 1. Brain MRI of the patient. At 1 year and 6 months of age, (a) hypoplasia of the corpus callous was observed on T1-weighted imaging, (b) mild myelination delay characterized by diffuse high-intensity areas was noted throughout the cerebral white matter in the frontal lobe, and (c) hypoplasia of the hippocampus was observed on T2-weighted imaging. At 3 years and 6 months of age (d–f), both sides of the inferior horn of the lateral ventricles were widened and hypoplasia of the hippocampus of both sides was marked on T2-weighted FLAIR imaging.
A
B
Patient Asn
Ala
Leu
Ile
Met
Met
Ala
Asn
Control Asn
Ala
Leu
Ile
Met
Met
Ala
Homo sapiens
kppfsynalimmairqspek
181–200
Mus musculus
kppfsynalimmairqspek
172–191
Rattus norvegicus
kppfsynalimmairqspek
172–191
Gallus gallus
kppfsynalimmairqspek
143–162
Xenopus tropicalis
kppfsynalimmairqspek
124–143
Danio rerio
kppfsynalimmairqspek
113–132
C
p.Ile190Asn
1
181 275 DNA binding domain
489
Fig. 2. (a) A novel missense mutation in FOXG1 was identified in the patient. A substitution of T to A at position 569 changed the codon for Ile at position 190 to that for Asn, (b) Amino acid sequence alignment of FOXG1 proteins from various species. The Ile residue at position 190 that was mutated in this patient is conserved between species, (c) Schematic representation of the FOXG1 protein and location of the Ile190Asn mutation. This mutation is located within the DNA-binding domain of the FOXG1 protein.
FOXG1 mutation in a boy with a congenital variant of RTT and a hypoplastic hippocampus and compared the clinical features with those of previous cases. 2. Case report The patient, a 1-year-old boy, was born to nonconsanguineous, healthy parents at 40 weeks gestation after an uneventful pregnancy. His birth weight and
length were 2850 g ( 0.4 SD) and 49.7 cm (+0.3 SD), respectively. His occipitofrontal circumference (OFC) was 31.5 cm ( 1.3 SD). There was no significant family medical history. He had developed with no complications during the neonatal period and head control was noted 4 months after birth. However, he was never able to roll over or sit up by himself. Internal strabismus had been observed. At 1 year old, the patient developed loss of head control and showed severe intellectual disability
Please cite this article in press as: Harada K et al. Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.07.007
K. Harada et al. / Brain & Development xxx (2017) xxx–xxx
3
Table 1 A comparison of the clinical features of the present patient with those of previously reported cases with FOXG1 point mutations. Ariani et al. (2008) [2]
Mencarelli et al. (2010) [3]
Bahibuisson et al. (2010) [4]
Philippe et al. (2010) [5]
Le Guen et al. (2011) [6]
De Filippis et al. (2012) [7]
This case
Number of cases Sex Age range, years Normal OFC at birth
2 Female 7, 22 Yes, 34 cm
2 Female 4–5.8 Yes, 31.7– 34 cm
2 Female 10, 22 Yes, 34 cm
1 Male 3 Yes, 33 cm
2 Female 12, 31 Yes
1 Male 1 Yes, 31.5 cm
Deceleration of head growth from birth Regression Severe intellectual disability Relative preservation of eye contact Hypotonia
Yes
4 Female 3–13 ¾ Yes, 32.5– 34 cm (1 N/ A) Yes
½ Yes
Yes
Yes
½ Yes
Yes
N/A Yes
Yes Yes
No Yes
Yes Yes
No Yes
Yes ½ Yes
Yes Yes
N/A
¼ Yes (1 N/ A)
Yes
No (1 N/ A)
Yes
No (1 N/A)
No
Yes
2/4 Yes (1 N/A) 2/4 Yes No ¾ Yes (1 N/ A) ¾ Yes (1 N/ A) 2/4 Yes (18 months, N/A) 2/4 Yes (1 N/A) 2/4 Yes (1 N/A) ¾ Yes ¼ Yes (3 N/ A) 2/4 Yes (1 N/A) No
Yes
½ Yes
Yes
½ Yes
Yes
½ Yes No Yes
No ½ Yes ½ Yes
No No Yes
½ Yes Yes ½ Yes
No No Yes
Yes
Yes
Yes
N/A
Yes
½ Yes (4 and 18)
½ Yes (2 years)
No
½ Yes (7 months)
Yes (1 year)
Yes
Yes
Yes
Yes
Yes
Yes
½ Yes
Yes
No
Yes
Yes ½ Yes
½ Yes Yes
Yes Yes
No No
No Yes
No
½ Yes
Yes
Yes
Yes
No
No
No
No
Yes
¼ Yes (3 N/ A) 2/4 Yes (1 N/A) ¼ Yes (3 N/ A)
Yes
½ Yes
Yes
No
Yes
½ Yes
½ Yes
Yes
No
Yes
½ Yes
No
Yes
No
Yes
N/A
N/A
Autistic features
N/A
Yes (midface hypoplasia, slight upslanting palpebral fissures, bulbous nasal tip, anteverted nares, everted lower lip, and straight hair)
Yes (tented upper lips)
Scoliosis Ability to walk Poor to absent purposeful hand use Ophthalmological abnormalities Seizures (age of onset)
Yes No Yes
Hand stereotypes
Yes
Jerky movements of the upper limbs Bruxism Mood lability
Yes
Sleep disturbance
No
Hypoplastic hippocampus Delayed myelination or hypomyelination Hypoplastic corpus callosum Frontal and temporal atrophy with gyral simplification Dysmorphic features
No
N/A Yes (2, 14 years)
Yes Yes
N/A Yes Yes
N/A
N/A, not applicable.
including regression with no expressive language. He was unable to communicate through eye contact. His OFC was 40.5 cm ( 4.0 SD), showing severe microcephaly. There were no physical findings except a tented upper lip, internal strabismus, and a single transverse palmar crease. The karyotype was 46, XY and microarray comparative genomic hybridization results were normal. No other abnormality was noted on blood testing.
He demonstrated repetitive thrusting of the tongue and dyskinetic involuntary movements including peculiar jerky movements of the upper limbs. He showed extreme disturbance of sleep: he sometimes could not sleep for 2 or 3 days consecutively. His inappropriate laughing disturbed his sleep. At 1 year and 6 months of age, he experienced unprovoked tonic-clonic seizures. There were no abnormalities regarding his blood, cerebrospinal fluid,
Please cite this article in press as: Harada K et al. Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.07.007
4
K. Harada et al. / Brain & Development xxx (2017) xxx–xxx
or interictal electroencephalography. However, brain MRI revealed hypoplasia of the corpus callosum, delayed myelination mainly in the frontal lobe, and a hypoplastic hippocampus (Fig. 1). He again experienced the same kind of seizure when he was 2 years and 3 months old. Brain MRI showed not only obvious delayed myelination, but also atrophy in the frontal lobe. Brain MRI when he was 3 years and 6 months old showed an obvious hypoplastic hippocampus (Fig. 1). He was diagnosed with a congenital variant of RTT based on the history and clinical features. To confirm the diagnosis, after written informed consent had been obtained from his parents, genomic DNA was extracted from the peripheral blood leukocytes of the patient and used for mutation screening. The patient had a novel missense mutation in FOXG1 (c. 569T>A, numbered according to NCBI reference sequence: NC_000014.8, p. Ile190Asn) within the DNA-binding forkhead domain, which affects a residue highly conserved across different species (Fig. 2). 3. Discussion We identified a novel FOXG1 mutation in a boy with a congenital variant of RTT and compared its clinical features with those of other cases reported previously (Table 1). Our case showed not only the typical cerebral abnormalities of a congenital variant of RTT, but also a hypoplastic hippocampus. The salient clinical features are acquired microcephaly, severe intellectual disability, hypotonia, limited motor function, poor to absent purposeful hand use, and repetitive jerky movements of the upper limbs. Many cases of the congenital variant of RTT do not show a regression period because of a severe developmental delay from early infancy. Regression could be identified in only 9 of 14 cases, including the present case. As salient brain MRI features, a hypoplastic corpus callosum [2–6], delayed myelination or hypomyelination [3–6], and frontal and temporal atrophy with gyral simplification [2–4,6] are known from previously reported cases with FOXG1 point mutations. However, no clinical report had described a hippocampal abnormality. In this case, severe hypoplastic hippocampus was seen from coronal T2-weighted FLAIR MR imaging obtained when he was 3 years. Both sides of the inferior horn of the lateral ventricles were widened and the hippocampal volume was less than half. Although there were no local indications, the overall appearance indicated hypoplasia. In a previous study, the hippocampal formations on the right side were larger than those on the left for all subjects aged 3 weeks to 14 years [8]. However, in this case, the hypoplasia of the right side was severe compared with that of the left side. We consider that the hypoplastic hippocampus was caused by
genetic factor. He had no hypoxia or refractory seizure history before the first MRI was taken. The hippocampal formation refers to the functional unit consisting of the hippocampus, dentate gyrus, and subiculum. The current study suggests that FOXG1 is strongly expressed in the postnatal telencephalon within the two known regions of postnatal neurogenesis. They are the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. FOXG1+/ mice show a 60% decrease in the total number of hippocampal dentate granule cells, which is related to a loss of dentate gyrus neurogenesis [9], and thus FOXG1 plays an essential role in the postnatal development of the dentate gyrus [10]. Changes in the hippocampus have already been reported in mouse models of the FOXG1 aberration. So far, there has been no report of patients with the congenital variant of RTT showing changes in the hippocampus on MRI. Although the mechanistic connection between the FOXG1 aberration and failed postnatal dentate gyrus neurogenesis remains to be elucidated, the MRI findings in our report may provide new insights into the pathophysiology of the congenital variant of RTT. References [1] Helen L, Stuart C, Jenny D. Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol 2017;13:37–51. [2] Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA, Spanhol-Rosseto A, et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet 2008;83:89–93. [3] Mencarelli MA, Spanhol-Rosseto A, Artuso R, Rondinella D, De Filippis R, Bahi-Buisson N, et al. Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J Med Genet 2010;47:49–53. [4] Bahi-Buisson N, Nectoux J, Girard B, Van Esch H, De Ravel T, Boddaert N, et al. Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant. Neurogenetics 2010;11:241–9. [5] Philippe C, Amsallem D, Francannet C, Lambert L, Saunier A, Verneau F, et al. Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. J Med Genet 2010;47:59–65. [6] Le Guen T, Bahi-Buisson N, Nectoux J, Boddaert N, Fichou Y, Diebold B, et al. A FOXG1 mutation in a boy with congenital variant of Rett syndrome. Neurogenetics 2011;12:1–8. [7] De Filippis R, Pancrazi L, Bjørgo K, Rosseto A, Kleefstra T, Grillo E, et al. Expanding the phenotype associated with FOXG1 mutations and in vivo FoxG1 chromatin-binding dynamics. Clin Genet 2012;82:395–403. [8] Utsunomiya H, Takano K, Okazaki M, Mitsudome A. Development of the temporal lobe in infants and children: analysis by MR-based volumetry. AJNR Am J Neuroradiol 1999;20:717–23. [9] Shen L, Nam HS, Song P, Moore H, Anderson SA. FOXG1 haploinsufficiency results in impaired neurogenesis in the postnatal hippocampus and contextual memory deficits. Hippocampus 2006;16:875–90. [10] Tian C, Gong Y, Yang Y, Shen W, Wang K, Liu J, et al. FOXG1 has an essential role in postnatal development of the dentate gyrus. J Neurosci 2012;32:2931–49.
Please cite this article in press as: Harada K et al. Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.07.007
Case Report
Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation Kotoha Harada a,⇑, Mayumi Yamamoto a, Yukihiko Konishi b, Kaori Koyano b, Satoru Takahashi c, Masanori Namba d, Takashi Kusaka b b
a Department of Pediatrics, Shodoshima Central Hospital, Japan Department of Pediatrics, Faculty of Medicine, Kagawa University, Japan c Department of Pediatrics, Asahikawa Medical University, Japan d Department of Pediatrics, Kagawa Rehabilitation Center, Japan
Received 12 January 2017; received in revised form 24 June 2017; accepted 17 July 2017
Abstract The forkhead box G1 (FOXG1) gene encodes a brain-specific transcription factor and is associated with a congenital variant of atypical Rett syndrome (RTT); several FOXG1 mutations have been identified. The congenital variant of RTT shows a hypoplastic corpus callosum, delayed myelination, and frontal and temporal atrophy. Although no report has described a hippocampal abnormality in humans, the current study suggests that FOXG1 also regulates neurogenesis in the postnatal hippocampus. In the present case, severe developmental delay was observed in a patient with a congenital variant of RTT from about 4 months, in conjunction with acquired microcephaly, hypotonia, limited motor function, absent purposeful hand use, and repetitive jerky movements of the upper limbs. A novel missense mutation was identified in FOXG1 on gene analysis (c. 569T>A, p. Ile190Asn). The patient showed not only the typical cerebral abnormalities of a congenital variant of RTT, but also a hypoplastic hippocampus. This novel mutation and cerebral findings may provide new insights into the pathophysiology of the congenital variant of RTT. Ó 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Rett syndrome; Congenital variant; Hypoplastic hippocampus; FOXG1; Novel missense mutation
1. Introduction Rett syndrome (RTT) is a neurodevelopmental disorder associated with diverse neurologic manifestations in an age-dependent manner. It is diagnosed based on clinical symptoms, and regression of purposeful hand use and language function, abnormal gait, and stereotypical movement of the hands are essential features. Patients
⇑ Corresponding author at: Department of Pediatrics, Shodoshima Central Hospital, 2060-1 Ikeda, Shodoshima-cho, Shozu-gun, Kagawa 761-4301, Japan. E-mail address: [email protected] (K. Harada).
whose clinical course shows similar but also different features are reported to have atypical RTT. In a type of atypical RTT, the congenital variant—caused by an aberrant forkhead box G1 (FOXG1) gene and now be considered as Rett-related disorders [1]—is present and developmental delay is observed soon after birth. In addition, acquired microcephaly, repetitive thrusting of the tongue, and stereotypical movements accompanied by jerky movements of the upper limbs are the main characteristics. A hypoplastic corpus callosum, delayed myelination, and frontal and temporal atrophy are the salient brain MRI features. No report has described a hippocampal abnormality. We identified a novel
http://dx.doi.org/10.1016/j.braindev.2017.07.007 0387-7604/Ó 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Harada K et al. Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.07.007
2
K. Harada et al. / Brain & Development xxx (2017) xxx–xxx
A
B
D
C
E
F
Fig. 1. Brain MRI of the patient. At 1 year and 6 months of age, (a) hypoplasia of the corpus callous was observed on T1-weighted imaging, (b) mild myelination delay characterized by diffuse high-intensity areas was noted throughout the cerebral white matter in the frontal lobe, and (c) hypoplasia of the hippocampus was observed on T2-weighted imaging. At 3 years and 6 months of age (d–f), both sides of the inferior horn of the lateral ventricles were widened and hypoplasia of the hippocampus of both sides was marked on T2-weighted FLAIR imaging.
A
B
Patient Asn
Ala
Leu
Ile
Met
Met
Ala
Asn
Control Asn
Ala
Leu
Ile
Met
Met
Ala
Homo sapiens
kppfsynalimmairqspek
181–200
Mus musculus
kppfsynalimmairqspek
172–191
Rattus norvegicus
kppfsynalimmairqspek
172–191
Gallus gallus
kppfsynalimmairqspek
143–162
Xenopus tropicalis
kppfsynalimmairqspek
124–143
Danio rerio
kppfsynalimmairqspek
113–132
C
p.Ile190Asn
1
181 275 DNA binding domain
489
Fig. 2. (a) A novel missense mutation in FOXG1 was identified in the patient. A substitution of T to A at position 569 changed the codon for Ile at position 190 to that for Asn, (b) Amino acid sequence alignment of FOXG1 proteins from various species. The Ile residue at position 190 that was mutated in this patient is conserved between species, (c) Schematic representation of the FOXG1 protein and location of the Ile190Asn mutation. This mutation is located within the DNA-binding domain of the FOXG1 protein.
FOXG1 mutation in a boy with a congenital variant of RTT and a hypoplastic hippocampus and compared the clinical features with those of previous cases. 2. Case report The patient, a 1-year-old boy, was born to nonconsanguineous, healthy parents at 40 weeks gestation after an uneventful pregnancy. His birth weight and
length were 2850 g ( 0.4 SD) and 49.7 cm (+0.3 SD), respectively. His occipitofrontal circumference (OFC) was 31.5 cm ( 1.3 SD). There was no significant family medical history. He had developed with no complications during the neonatal period and head control was noted 4 months after birth. However, he was never able to roll over or sit up by himself. Internal strabismus had been observed. At 1 year old, the patient developed loss of head control and showed severe intellectual disability
Please cite this article in press as: Harada K et al. Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.07.007
K. Harada et al. / Brain & Development xxx (2017) xxx–xxx
3
Table 1 A comparison of the clinical features of the present patient with those of previously reported cases with FOXG1 point mutations. Ariani et al. (2008) [2]
Mencarelli et al. (2010) [3]
Bahibuisson et al. (2010) [4]
Philippe et al. (2010) [5]
Le Guen et al. (2011) [6]
De Filippis et al. (2012) [7]
This case
Number of cases Sex Age range, years Normal OFC at birth
2 Female 7, 22 Yes, 34 cm
2 Female 4–5.8 Yes, 31.7– 34 cm
2 Female 10, 22 Yes, 34 cm
1 Male 3 Yes, 33 cm
2 Female 12, 31 Yes
1 Male 1 Yes, 31.5 cm
Deceleration of head growth from birth Regression Severe intellectual disability Relative preservation of eye contact Hypotonia
Yes
4 Female 3–13 ¾ Yes, 32.5– 34 cm (1 N/ A) Yes
½ Yes
Yes
Yes
½ Yes
Yes
N/A Yes
Yes Yes
No Yes
Yes Yes
No Yes
Yes ½ Yes
Yes Yes
N/A
¼ Yes (1 N/ A)
Yes
No (1 N/ A)
Yes
No (1 N/A)
No
Yes
2/4 Yes (1 N/A) 2/4 Yes No ¾ Yes (1 N/ A) ¾ Yes (1 N/ A) 2/4 Yes (18 months, N/A) 2/4 Yes (1 N/A) 2/4 Yes (1 N/A) ¾ Yes ¼ Yes (3 N/ A) 2/4 Yes (1 N/A) No
Yes
½ Yes
Yes
½ Yes
Yes
½ Yes No Yes
No ½ Yes ½ Yes
No No Yes
½ Yes Yes ½ Yes
No No Yes
Yes
Yes
Yes
N/A
Yes
½ Yes (4 and 18)
½ Yes (2 years)
No
½ Yes (7 months)
Yes (1 year)
Yes
Yes
Yes
Yes
Yes
Yes
½ Yes
Yes
No
Yes
Yes ½ Yes
½ Yes Yes
Yes Yes
No No
No Yes
No
½ Yes
Yes
Yes
Yes
No
No
No
No
Yes
¼ Yes (3 N/ A) 2/4 Yes (1 N/A) ¼ Yes (3 N/ A)
Yes
½ Yes
Yes
No
Yes
½ Yes
½ Yes
Yes
No
Yes
½ Yes
No
Yes
No
Yes
N/A
N/A
Autistic features
N/A
Yes (midface hypoplasia, slight upslanting palpebral fissures, bulbous nasal tip, anteverted nares, everted lower lip, and straight hair)
Yes (tented upper lips)
Scoliosis Ability to walk Poor to absent purposeful hand use Ophthalmological abnormalities Seizures (age of onset)
Yes No Yes
Hand stereotypes
Yes
Jerky movements of the upper limbs Bruxism Mood lability
Yes
Sleep disturbance
No
Hypoplastic hippocampus Delayed myelination or hypomyelination Hypoplastic corpus callosum Frontal and temporal atrophy with gyral simplification Dysmorphic features
No
N/A Yes (2, 14 years)
Yes Yes
N/A Yes Yes
N/A
N/A, not applicable.
including regression with no expressive language. He was unable to communicate through eye contact. His OFC was 40.5 cm ( 4.0 SD), showing severe microcephaly. There were no physical findings except a tented upper lip, internal strabismus, and a single transverse palmar crease. The karyotype was 46, XY and microarray comparative genomic hybridization results were normal. No other abnormality was noted on blood testing.
He demonstrated repetitive thrusting of the tongue and dyskinetic involuntary movements including peculiar jerky movements of the upper limbs. He showed extreme disturbance of sleep: he sometimes could not sleep for 2 or 3 days consecutively. His inappropriate laughing disturbed his sleep. At 1 year and 6 months of age, he experienced unprovoked tonic-clonic seizures. There were no abnormalities regarding his blood, cerebrospinal fluid,
Please cite this article in press as: Harada K et al. Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.07.007
4
K. Harada et al. / Brain & Development xxx (2017) xxx–xxx
or interictal electroencephalography. However, brain MRI revealed hypoplasia of the corpus callosum, delayed myelination mainly in the frontal lobe, and a hypoplastic hippocampus (Fig. 1). He again experienced the same kind of seizure when he was 2 years and 3 months old. Brain MRI showed not only obvious delayed myelination, but also atrophy in the frontal lobe. Brain MRI when he was 3 years and 6 months old showed an obvious hypoplastic hippocampus (Fig. 1). He was diagnosed with a congenital variant of RTT based on the history and clinical features. To confirm the diagnosis, after written informed consent had been obtained from his parents, genomic DNA was extracted from the peripheral blood leukocytes of the patient and used for mutation screening. The patient had a novel missense mutation in FOXG1 (c. 569T>A, numbered according to NCBI reference sequence: NC_000014.8, p. Ile190Asn) within the DNA-binding forkhead domain, which affects a residue highly conserved across different species (Fig. 2). 3. Discussion We identified a novel FOXG1 mutation in a boy with a congenital variant of RTT and compared its clinical features with those of other cases reported previously (Table 1). Our case showed not only the typical cerebral abnormalities of a congenital variant of RTT, but also a hypoplastic hippocampus. The salient clinical features are acquired microcephaly, severe intellectual disability, hypotonia, limited motor function, poor to absent purposeful hand use, and repetitive jerky movements of the upper limbs. Many cases of the congenital variant of RTT do not show a regression period because of a severe developmental delay from early infancy. Regression could be identified in only 9 of 14 cases, including the present case. As salient brain MRI features, a hypoplastic corpus callosum [2–6], delayed myelination or hypomyelination [3–6], and frontal and temporal atrophy with gyral simplification [2–4,6] are known from previously reported cases with FOXG1 point mutations. However, no clinical report had described a hippocampal abnormality. In this case, severe hypoplastic hippocampus was seen from coronal T2-weighted FLAIR MR imaging obtained when he was 3 years. Both sides of the inferior horn of the lateral ventricles were widened and the hippocampal volume was less than half. Although there were no local indications, the overall appearance indicated hypoplasia. In a previous study, the hippocampal formations on the right side were larger than those on the left for all subjects aged 3 weeks to 14 years [8]. However, in this case, the hypoplasia of the right side was severe compared with that of the left side. We consider that the hypoplastic hippocampus was caused by
genetic factor. He had no hypoxia or refractory seizure history before the first MRI was taken. The hippocampal formation refers to the functional unit consisting of the hippocampus, dentate gyrus, and subiculum. The current study suggests that FOXG1 is strongly expressed in the postnatal telencephalon within the two known regions of postnatal neurogenesis. They are the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. FOXG1+/ mice show a 60% decrease in the total number of hippocampal dentate granule cells, which is related to a loss of dentate gyrus neurogenesis [9], and thus FOXG1 plays an essential role in the postnatal development of the dentate gyrus [10]. Changes in the hippocampus have already been reported in mouse models of the FOXG1 aberration. So far, there has been no report of patients with the congenital variant of RTT showing changes in the hippocampus on MRI. Although the mechanistic connection between the FOXG1 aberration and failed postnatal dentate gyrus neurogenesis remains to be elucidated, the MRI findings in our report may provide new insights into the pathophysiology of the congenital variant of RTT. References [1] Helen L, Stuart C, Jenny D. Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol 2017;13:37–51. [2] Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA, Spanhol-Rosseto A, et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet 2008;83:89–93. [3] Mencarelli MA, Spanhol-Rosseto A, Artuso R, Rondinella D, De Filippis R, Bahi-Buisson N, et al. Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J Med Genet 2010;47:49–53. [4] Bahi-Buisson N, Nectoux J, Girard B, Van Esch H, De Ravel T, Boddaert N, et al. Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant. Neurogenetics 2010;11:241–9. [5] Philippe C, Amsallem D, Francannet C, Lambert L, Saunier A, Verneau F, et al. Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. J Med Genet 2010;47:59–65. [6] Le Guen T, Bahi-Buisson N, Nectoux J, Boddaert N, Fichou Y, Diebold B, et al. A FOXG1 mutation in a boy with congenital variant of Rett syndrome. Neurogenetics 2011;12:1–8. [7] De Filippis R, Pancrazi L, Bjørgo K, Rosseto A, Kleefstra T, Grillo E, et al. Expanding the phenotype associated with FOXG1 mutations and in vivo FoxG1 chromatin-binding dynamics. Clin Genet 2012;82:395–403. [8] Utsunomiya H, Takano K, Okazaki M, Mitsudome A. Development of the temporal lobe in infants and children: analysis by MR-based volumetry. AJNR Am J Neuroradiol 1999;20:717–23. [9] Shen L, Nam HS, Song P, Moore H, Anderson SA. FOXG1 haploinsufficiency results in impaired neurogenesis in the postnatal hippocampus and contextual memory deficits. Hippocampus 2006;16:875–90. [10] Tian C, Gong Y, Yang Y, Shen W, Wang K, Liu J, et al. FOXG1 has an essential role in postnatal development of the dentate gyrus. J Neurosci 2012;32:2931–49.
Please cite this article in press as: Harada K et al. Hypoplastic hippocampus in atypical Rett syndrome with a novel FOXG1 mutation. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.07.007